DE19812413C1 - Transdermal therapeutic system for administration of oxybutynin - Google Patents

Abstract

The invention relates to a transdermal therapeutic system (TTS) for transcutaneous administration of oxybutynin over a period of several days, in addition to a method for the production thereof without the use of solvents. The TTS contains a matrix mass containing oxybutynin in the form of a self-adhesive layer. Said matrix mass consists of (meth)-acrylic polymers containing ammoniac groups, at least one citric acid ester and 5-25 wt. % oxybutynin.

Description

The present invention relates to a transdermal therapeutic system (TTS) for transcutaneous administration of oxybutynin over several days as well as a procedure its manufacture without the use of solvents.

The bioavailability of orally or intravenously administered active ingredients is often unsatisfied digend. The hepatic metabolism of many active substances can occur at the first liver pass say about undesirable concentration ratios, toxic by - products and lead to a reduction in the effectiveness or even to a loss of activity. Compared to oral ver administration, transdermal administration of active substances has various advantages. The Active substance supply can be better controlled over a longer period of time, as a result of which high Fluctuations in blood levels can be avoided. In addition, the required therapy effective dose are usually significantly reduced. In addition, a patch from Patients often preferred more than once or several times a day Tablets.

In the past, the aforementioned disadvantages have not been overcome transdermal administration of active substances by a variety of transdermal Therapeu table systems (TTS) with different structures for different active substances Therapy of different diseases taken into account.

So describe the following technical documents for a broad Diversity of systemically or locally reacting active substances, their parenteral administration either on the basis of dose-controlling or generally releasing systems. Examples include U.S. P. (U.S. Patent Numbers) 3,598,122 A; 3,598,123 A; 3,731,683 A; 3,797,494 A; 4,031,894 A; 4,201,211 A; 4,286,592 A; 4,314,557 A; 4,379,454 A; 4,435,180 A; 4,559,222 A; 4,568,343 A; 4,573,995 A, 4,588,580 A; 4,645,502 A; 4,702,282 A; 4,788,062 A; 4,816,258 A; 4,849,226 A; 4,908,027 A; 4,943,435 A and 5,004,610 A.  

In the late 1960s this century was originally theoretical been taken that any active ingredient with a short half-life but high effectiveness and good skin patency for safe and effective administration by means of a TTS is suitable. These initial expectations regarding the possibilities of However, transdermal drug delivery using TTS could not be met become. This is mainly due to the fact that the skin is naturally is endowed with an unmanageable variety of properties to their function as an intact barrier against the penetration of non-body substances in to maintain the body. (See: Transdermal Drug Delivery: Problems and Possibilities, B.M. Knepp et al., CRC Critical Review and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987)).

Therefore, transdermal administration is only available for those few active substances Available that has a suitable combination of many favorable characteristics exhibit. For a specific active ingredient, these are required characteristics that to ensure safe and effective transdermal administration, but not predictable.

The requirements for an active ingredient suitable for transdermal administration are:

• - skin patency,
• - the adhesive does not impair the adhesive properties of the patch,
• - avoiding skin irritation,
• - avoid allergic reactions,
• - favorable pharmacokinetic properties,
• - favorable pharmacodynamic properties,
• - a relatively wide therapeutic window,
• - Metabolism properties that are consistent with the therapeutic application are continuous gift.

There is no doubt that the above list of requirements is not exhaustive. So that one Active ingredient for transdermal administration is available "correct" combination of all these requirements is desirable.  

The above for the active ingredients applies in the same way for the respective active ingredient containing TTS composition and its constructive structure.

Usually the Transdermal Therapeutic Systems (TTS) around plasters with an impermeable top layer, a removable protective layer and an active substance-containing matrix or an active substance-containing reservoir with semiper meabler membrane are equipped. In the first case, they are used as matrix patches, in in the second case referred to as the membrane system.

Polyester, polypropylene, polyethylene, poly are usually used for the cover layer urethane etc. used, which can also be metallized or pigmented. For those from pullable protective layer come u. a. Polyester, polypropylene or paper with sili con and / or polyethylene coating into consideration.

For the pharmaceutically or medically customary active substance-containing matrices Fabrics based on polyacrylate, silicone, polyisobutylene, butyl rubber, styrene / Butadiene copolymer or styrene / isoprene copolymer used.

The membranes used in membrane systems can be microporous or semiper meabel and are usually based on an inert polymer, in particular Polypropylene, polyvinyl acetate or silicone are formed.

While the active ingredient-containing matrix compositions can be self-adhesive, however, there are also active substance-dependent substances depending on the active substance used Matrices that are not self-adhesive, as a result of which the plaster or TTS constructively must be provided with an overtape.

Skin pens are often used to ensure the required flux rate of the active ingredient Trationsenhancer such as aliphatic, cycloaliphatic and / or aromatic-aliphatic Alcohols, each mono- or polyvalent and each containing up to 8 carbon atoms Alcohol / water mixture, a saturated and / or unsaturated fatty alcohol with each 8 to 18 carbon atoms, each a saturated and / or unsaturated fatty acid 8 to 18 carbon atoms and / or their esters and vitamins required as an additive.  

Furthermore, stabilizers such as polyvinylpyrrolidone, α-tocopherol succinate, Propyl gallate, methionine, cysteine and / or cysteine hydrochloride, the active ingredient Matrix added.

As the above list shows, there are numerous TTS constructions and for this used materials known. However, there are many interacting needs too take into account if a medication in the form of a TTS is a medical Need should suffice.

The following problems have to be considered when developing active substance-containing TTS:

• 1. The skin permeability for the active ingredient is too low to be therapeutically necessary to achieve the penetration rate and / or the lag time until Reaching the therapeutically required plasma level is too long, with the result that that skin penetration-accelerating additives must be administered.
• 2. The drug-laden and possibly additionally loaded with skin penetration enhancers Polymer matrix is not physically stable after long storage. In particular, can an active ingredient recrystallization occur which leads to an uncontrollable decrease of the drug release capacity of the TTS.
• 3. A high loading of the polymeric carrier with active ingredient and / or skin penis trationsenhancern difficult with self-adhesive polymer films the setting op temporal adhesive properties of the transdermal system.
• 4. The drug absorption rate drops in applications over several days in not ak acceptable way, so that additional control layers and / or components required are.
• 5. If active substance-laden layers are made from organic solutions, this occurs Problem of remaining solvent residues in the active ingredient-containing layer the drying process. In addition, there is a risk of an undesirable one Evaporation of volatile auxiliaries during manufacture. Because for reasons the physical stability and skin tolerance of the system as a rule If the aim is to be completely solvent-free, the reservoir must be given  if built up in several layers. This in turn leads to an increase production costs.
• 6. It is also known from the literature that the penetration promotion by Skin frequently used fluctuating fatty acid esters of polyhydric alcohols Have quality and impure blending agents. This leads to poor reproducibility real increases in penetration (Burkoth et al. 1996, DE 196 22 902 A1).

The problems described therefore require a large number of embodiments Transdermal therapeutic systems based on this in the prior art Reflect area.

A more recent overview of this is given, for example, by U.S. P 5,662,926 A (Wick et al., 1997). This document describes transdermal systems that have a monolithic, ther contain plastic polymer film in which an active ingredient, preferably nicotine, is homogeneously distributed, and a process for the solvent-free production thereof Active ingredient-containing layer by mixing the active ingredient with the polymer Carrier material in the polymer melt at temperatures from 170 ° C to 200 ° C. For Fixing the matrix film containing the active ingredient on the skin provides additional contact adhesive film that is applied to the active substance matrix and, if necessary, additionally a larger area plaster, which on the matrix side facing away from the skin on the drug-containing polymer film is applied.

Similar construction principles for transdermal systems or active substance patches are also in WO 93/23025 A1 and WO 95/09007 A1 for plaster preparations containing oxybutynin described. According to WO 95/09007 A1, the skin penetration can be caused by oxybutynin Polymer matrices increased by monoglycerides mixed with esters of lactic acid be, the these penetration enhancer mixtures little or no skin should generate irritation.

The above PCT documents describe ethylene Vinyl acetate (EVA) copolymers are used for the incorporation of oxybutynin in one suitable organic solvent or melted by heating. Films are then created by coating and removal of the solvent or by calendering the homogeneous polymer / active ingredient / Enhancer mix.  

For incontinence treatment, according to WO 93123025 A1, oxybutynin plasma levels in of the order of 0.5-2 ng / ml, corresponding to a release rate from 40-200 µg / h, preferably 80-160 µg / h.

According to U.S. P 5,601,839 A can also use these self-adhesive permeation rates monolithic systems achieved by using triacetin as a penetration enhancer become.

Polymers based on acrylic acid esters and methacrylic acid esters are of particular interest because of their relatively good absorption and release capacity for a large number of active ingredients in the development of transdermal systems. In order to avoid the use of solvents in the production of matrix systems based on poly (meth) acrylate, DE 43 10 012 A1 describes a dermal therapeutic system in which one or more layers are composed of mixtures of poly (meth) acrylates and from which Melt are produced and the first mixture component consists of (meth) acrylic polymers that contain functional groups, the second mixture component regulates the flow behavior and contains only insignificant amounts of functional groups. The composite systems with poly (meth) acrylates with functional groups are intended to enable controlled delivery of the active ingredient (s) to or through the skin and a simple manner of production. Furthermore, the active substance-containing formulations obtained by combining poly (meth) acrylates with a low glass temperature are said to have properties of a pressure-sensitive skin pressure sensitive adhesive. Experience has shown that the advantages of manufacturing compared to solvent-based processes with such systems are offset by a number of disadvantages that are caused by:

• 1. Long-term thermal stress on all TTS components in ( 1 ) the manufacture of the polymer melt, ( 2 ) the homogeneous incorporation of the active ingredient (s) and / or ( 3 ) the coating of the hot active ingredient-containing mass on suitable carrier materials with increased risk of degradation or decomposition reactions in the polymer melt and / or during storage of the active ingredient-containing polymer films.
• 2. Difficulties in optimizing the co- / adhesion balance of the poly (meth) acry latex layer for a multi-day application, because the Acry is cross-linked  latcopolymerisates by means of covalent bonds during the production of the active polymer matrix in the melt is not possible, combined with problems men caused by a cold flow of the polymer mass when applied to the skin and / or can occur during storage.

DE 196 53 606 A1 describes an adhesive and binder for TTS from each defined Mass fractions of components a) (meth) acrylate polymer, the quaternary ammonium may have groups, b) an organic di- or tricarboxylic acid and c) one Plasticizer that can be a citric acid trieste.

As the above list shows, there are many pavement constructions and ver known materials used. Nonetheless, for many people it still exists in transdermal areas Therapeutic systems processed active ingredients a great need, TTS available to provide that enable a therapeutically required delivery of active ingredients without to be structurally complex and an op represent a temporal relationship. This also applies to the active ingredient oxybutynin when it is trans cutan to be administered.

Oxybutynin is used therapeutically for the symptomatic treatment of hyperactivity of the Detrusors (hyperfunction of the bladder muscle) with frequent urge to urinate, increased urinating at night, compulsive urination, involuntary urination with or used without urge to urinate (incontinence). The transcutaneous application of oxybutynin by means of a TTS is desirable because bypassing the gastrointestinal tract and during the first passage through the liver, peak concentrations of oxybutynin in the blood were avoided be, which lead to the occurrence of undesirable effects such as dry mouth, Akkomoda dysfunction, nausea and dizziness. By bypassing the "first "Metabolism in the liver can be compared to oral administration by Biover Availability of oxybutynin can be increased, or the total dose reduced, the are required to achieve the therapeutically desired effect.

It is therefore an object of the present invention to avoid the aforementioned disadvantages of TTS with oxybutynin and to provide a structurally simple, skin-compatible, physically and chemically stable TTS for transcutaneous administration of oxybutynin with good adhesive properties over a longer storage and application period, the

• a) releases as much active ingredient as possible on and through the skin per unit area,
• b) does not contain a skin penetration enhancer,
• c) is solvent-free and with that
• d) the thermal load of the active ingredient oxybutynin in the manufacturing process briefly timely and as low as possible.

To solve this problem, a TTS and a method for its production without Use of solvents provided, its special composition tion surprisingly satisfies the aforementioned task. It contains one Oxybutynin-containing matrix mass in the form of a layer that is self-adhesive, the Matrix mass of (meth) acrylate copolymers containing ammonio groups, at least a citric acid triester and 5-25% by weight oxybutynin. The TTS can can be applied to the skin over several days.

The TTS according to the invention is therefore due to its special composition The addition of skin penetration enhancers is not necessary.

For the purposes of the invention, the terms and / or words mentioned below are understood as follows:

• a) "solvent-free":
  to produce the polymer matrices, no solvents are used which are largely removed again in the course of the production process, as is done in the so-called "solvent-based" process.
• b) "several days":
  the TTS can be applied to the skin for therapeutic use from 1 to 7, preferably 1 to 4 days.
• c) "short-term thermal exposure of the active ingredient:"
  The active substance added in solid form to the polymer matrix heated up to 150 ° C. is cooled to below its melting point in the polymer matrix within one minute.
• d) "fixed solution":
  the active pharmaceutical ingredient is molecularly dispersed in the polymer / lemon triester mixture.

According to a further embodiment according to the invention, the above-described TTS additionally with the exception of the release surface of its oxybutynin-containing matrix the skin of a larger, but drug-free skin patch for fixation on the Application area (overtape) be surrounded.

This structure has the advantage that the different skin types and climates Can be taken into account. Furthermore, on the one hand the cohesion / adhesion properties properties of the TTS, on the other hand the drug solubility, drug solution speed and the release behavior can be optimized largely separately.

According to a further development, the matrix mass preferably contains 10-20% by weight oxy butynin.

Finally, the oxybutynin-containing matrix mass can be a solid solution.

The formation of a solid solution of the oxybutynin in the ammonio group (Meth) acrylate polymers could not have been predicted and is all the more surprising than many Active ingredients in polymers no solid solutions (with molecularly disperse distribution) form, but store themselves in the form of solid particles in the respective polymer, which can be recognized by electron microscopy. In contrast to solid solutions show crystalline active ingredients also a Debye-Scherrer diagram.

According to a further embodiment of the invention, the oxybutynin-containing Ma trix mass preferably citric acid tributyl ester.

Finally, the oxybutynin-containing matrix mass can be a mixture of citric acid contain retributyl ester and citric acid triethyl ester.  

Because of the composition according to the invention and the construction of the TTS it is surprising that despite high drug concentrations of oxybutynin in the polymer matrix has sufficient physical stability of the system in the long term storage is guaranteed.

For the polymer used as the polymer matrix containing the active ingredient, it was not to be expected that that immediately after sticking on the TTS there is an intimate contact between active ingredient trix and skin is made, which is of the quality that a self over several days permanently adhesive TTS results, which both the therapeutic and the commercial liche, especially the business requirements.

The patient compliance is taken into account very well.

If you choose the embodiment with an active ingredient-free skin patch / overtape, are only very small skin patches with a width of only a few mm Adhesive edge required.

This is advantageous both economically and in terms of patient compliance. According to a further embodiment of the invention, the carrier film of the TTS has A metal vapor or oxide coating on the matrix side.

The TTS according to the invention can be produced using the method explained below be put.

A matrix mass containing oxybutynin that can be coated is produced by melt extrusion generated, the active ingredient in a hot up to 150 ° C polymer melt from (meth) acrylate copolymers containing ammonio groups and citric acid triesters is metered in continuously as a solid substance, so that a polymer melt with a Contents up to 25% by weight of oxybutynin and up to 33% by weight of citric acid triesters  is obtained and the hot active ingredient-containing polymer melt immediately after it has been made Continuous metering of the active ingredient onto a removable protective layer (= substrate, Carrier) is coated in a thickness of 0.02 to 0.4 mm and the resulting 2- Layer laminate is provided on the other side of the matrix with a cover layer.

The TTS with an additional skin patch or overtape is made as follows, manufactured.

A matrix mass containing oxybutynin that can be coated is produced by melt extrusion generated, the active ingredient in a hot up to 150 ° C polymer melt from (meth) acrylate copolymers containing ammonio groups and citric acid triesters is metered in continuously as a solid substance, so that a polymer melt with a Contents up to 25% by weight of oxybutynin and up to 33% by weight of citric acid triesters is obtained and the hot active ingredient-containing polymer melt immediately after it has been made Continuous metering of the active ingredient onto a removable protective layer (= substrate, Carrier) is coated in a thickness of 0.02 to 0.4 mm and the resulting 2- Layer laminate is provided on the other side of the matrix with a top layer and then a larger patch free of active ingredient to fix the TTS on the skin is applied.

The main advantage of the method according to the invention in contrast to So-called "batch process", in which the total quantity is weighed out Starting materials that are used to produce a batch (batch) and their Further processing to the pharmaceutical product in separate Production steps take place is that the one containing the active ingredient Polymer matrix (I) is produced without the use of organic solvents, and (II) the preparation of the active substance-containing matrix mass and its further processing to a layer containing active ingredients in a continuous and cost-saving Work done: Process times can be reduced to a few minutes. The Danger of decomposition reactions in the polymer melt containing the active ingredient can hereby be excluded. The active ingredient thus continues to correspond to Quality criteria of the DAB and / or the European or US. Pharmacopoeia. About It was surprisingly found that the full resolution and uniform Distribution of oxybutynin in the polymer melt despite the short process times below the process conditions further explained in the examples is guaranteed.  

Furthermore, the continuous production of the oxybutynin-containing polymer mass when transferring the manufacturing process from the laboratory to the production scale bypassing resulting problems (scaling-up problems), d. H. when increasing the Batch or batch size is for the production of the active ingredient-containing polymer melt and the laminate does not require a change to larger production facilities usually with time and costly installation, qualification and Validation work and possibly also recipe changes.

The structure of the TTS according to the invention is shown in drawings 1 and 2.

Drawing 1 shows the embodiment without overtape, consisting of active ingredient-containing polymer matrix ( 1 ), removable protective film ( 5 ) and cover film ( 2 ).

Drawing 2 shows the embodiment with overtape. In addition to the layers contained in the embodiment shown in drawing 1, an overtape consisting of carrier film ( 4 ) and adhesive film ( 3 ) is included.

The invention is illustrated by the following examples:

Example 1:

A twin-screw extruder equipped with three dosing units is fed continuously in successive process zones with Eudragit RS 100 (copolymer of ethyl acrylate and methyl methacrylate with approx. 5% trimethylammonioethyl methacrylate chloride), tri butyl citrate and oxybutynin, the mixture having a total throughput of 5 kg / h at one temperature is melt extruded from 110-140 ° C. From the metering unit 1 Eudragit RS 100 kg at a rate of 2.76 / h fed to the process portion of the extruder, 2 kg of tributyl citrate dosing at a rate of 1.49 / h and, finally, from dosage unit 3 oxybutynin in a rate of 0, 75 kg / h. After leaving the extruder, the hot polymer melt containing oxybutynin obtained is fed via a heated feed hose directly to the application head of the coating system in a continuous stream and, using a slot die, onto a 100 μm thick siliconized polyester film (= protective film ( 5 )) in a thickness of approx. 100 g per m ² (see drawing 1). After passing through a roller cooling device, the two-layer laminate is covered with an approximately 20 μm thick polyester film (= cover film ( 2 )).

12 cm ² pieces are then punched out of the sheet-like three-layer laminate obtained.

Example 2:

A twin-screw extruder equipped with three dosing units is fed continuously in successive process zones with Eudragit RS 100 (copolymer of ethyl acrylate and methyl methacrylate with approx. 5% trimethylammonioethyl methacrylate chloride), tri butyl citrate and oxybutynin, the mixture having a total throughput of 5 kg / h at one temperature is melt extruded from 110-140 ° C. From the metering unit 1 Eudragit RS 100 kg at a rate of 2.76 / h fed to the process portion of the extruder, 2 kg of tributyl citrate dosing at a rate of 1.49 / h and, finally, from dosage unit 3 oxybutynin in a rate of 0, 75 kg / h. After leaving the extruder, the hot polymer melt containing oxybutynin obtained is fed directly into the application head of the coating system in a continuous stream via a heated feed hose and, using a slot nozzle, onto an approximately 100 μm thick siliconized polyester film (= protective film ( 5 )) in a thickness of approx. 100 g per m ² (see drawing 2). After passing through a roller cooling device, the two-layer laminate is covered with an approximately 20 μm thick polyester film (cover film = (inner) carrier film ( 2 )).

The contours of 12 cm ² large matrix pieces are punched out from the sheet-like three-layer laminate obtained, the cover film ( 2 ) and active substance-containing polymer matrix ( 1 ), but not the protective film ( 5 ), being severed. The resulting intermediate webs are trimmed off. A self-adhesive overtape film with a 2-layer structure, consisting of an approx. 80 sqm thick adhesive film ( 3 ) based on a crosslinked acrylate copolymer and an (outer) carrier film ( 4 ), is made from the sheet-like laminate obtained with die-cut TTS matrices Padded polyurethane. The resulting laminate is punched out into 20 cm ² plasters consisting of components ( 1 ), ( 2 ), ( 3 ), ( 4 ), ( 5 ) according to drawing 2.

The twin-screw extruder used in Examples 1 and 2 has a defined one Length and has as a dosing unit or dosing station, spatially on the Longitudinal axis of the extruder separate addition devices for the to be used Fabrics. Furthermore, the length of the twin-screw extruder can be processed  zones can be divided that can meet different regulations. Example the difference in thermal setting of a process zone is relative called to another.

Flux measurements of oxybutynin in vitro a) Flux measurements through mouse skin

A TTS with a punched-out area of 2.5 cm ² is fixed in a horizontal diffusion cell on the horny layer side of the abdominal and back skin of hairless mice. Immediately afterwards, the acceptor chamber of the cell is filled with phosphate buffer solution pH 6.2 preheated to 32 ° C (Ph. Eur., PH 6.4 R; adjusted to pH 6.2 with phosphoric acid) and the release medium to 32 ± 0.5 ° C thermostatted.

At the sampling times (after 3, 6, 24, 30, 48, 54 and 72 hours) this will be Release medium against fresh medium thermostatted at 32 ± 0.5 ° C exchanged.

b) Flux measurements through human skin

The test was carried out according to Tiemessen (Harry LGM Tiemessen et al., Acta Pharm. Technol. 34 (1998), 99-101). According to the method described by this, the flux measurement was carried out in a flow cell on freshly prepared, approx. 200 µm thick human skin, which lies on the acceptor side on a silicone membrane (acceptor medium: phosphate buffer solution pH 6.2; thermostatted to 32 ± 0.5 ° C) .

Samples were taken after 3, 6, 9, 12, 15, 21, 24, 27, 30, 36, 42, 48, 54, 60, 66 and 72 hours.

The oxybutynin content in the release or acceptor medium described NEN models are determined using high pressure liquid chromatography. (Stationary phase: Supelcosil LC-8-DB, 150 mm × 4.6 mm, 3 µm; 45 ° C; eluent: 29 Parts by volume of acetonitrile and 71 parts by volume of a solution of 8 g of triethanolamine in 1000 ml of demineralized water, adjusted to pH 3.5 with phosphoric acid;  UV detection at 200 nm; Flow rate: 2.0 ml / min .; Injection volume: 25 µl).

The results of the tests are in Table 1 for Examples 1 and 2 shown. The comparison with the flux rates known from the prior art (cf. WO 95/09007 A1) of EVA-based polymer matrix systems shows that the Oxybutynin from the TTS according to the invention according to Examples 1 and 2 in "Steady-state" is released in installments through the skin compared to the state of technology are in the upper range or above. This is so far surprisingly, than the flux rates of EVA known from the prior art based polymer matrix systems can only be achieved by using special Additives that oppose the penetration of oxybutynin through human skin accelerate saturated solutions are included.

As the results in Table 1 also show, matrix systems according to of the present invention surprisingly an average skin permeation rate (flux) achieved, which is clearly above the saturation flows of oxybutynin from the in WO 93/23025 A1 described, low-viscosity solutions that are without Skin penetration enhancers (substances that increase skin permeability liquid for oxybutynin). It was with one acceptor medium tempered at 3 ° C lower than described in the literature data ben the flux measurement on the patches according to the invention even under certain conditions gene carried out, which are significantly less favorable for the penetration of active ingredients. Furthermore, Table 1 shows that with matrix systems according to Examples 1 and 2 the investigation period of 3 days a high utilization of the in polymeric carrier material contained total amount of active ingredient is reached.  

Table 1: Oxybutynin flux rates due to excised skin preparations (Examples 1 and 2)

Claims (8)

1. Transdermal therapeutic system (TTS) for the transcutaneous administration of oxybutynin over several days, characterized in that the TTS contains a self-adhesive, layered oxybutynin-containing matrix composition which consists of ammonio group-containing (meth) acrylate copolymers, at least one citric acid triester and 5-25 wt .-% oxybutynin exists. 2. Transdermal therapeutic system (TTS) for the transcutaneous administration of Oxybutynin for several days with a fixation aid for the TTS on the skin, characterized in that the TTS is a self-adhesive, layered Contains oxybutynin-containing matrix mass, which contains ammonio groups (Meth) acrylate copolymers, at least one citric acid triester and 5-25 % By weight of oxybutynin exists, and this, with the exception of its release surface at the application site of a larger active substance-free patch for fixation is surrounded on the skin. 3. TTS according to claims 1-2, characterized in that the oxybutynin-containing Matrix mass is a solid solution. 4. TTS according to claims 1-3, characterized in that the oxybutynin-containing Matrix mass contains citric acid tributyl ester. 5. TTS according to claims 1-4, characterized in that the oxybutynin-containing Matrix mass of citric acid tributyl ester mixed with citric acid triethyl ester contains. 6. TTS according to claims 1-5, characterized in that the carrier film matrix has a metal vapor or oxide coating on the side.   7. Method of Manufacturing a Transdermal Therapeutic System (TTS) for the transcutaneous administration of oxybutynin, characterized in that a polymer melt heated up to 150 ° C (Meth) acrylate copolymers and citric acid triesters as oxybutynin continuously Solid substance is metered in, so that a polymer melt with a content of get up to 25 wt .-% oxybutynin and up to 33 wt .-% citric acid triesters and the active ingredient-containing polymer melt immediately after the addition of the active ingredient in a thickness of 0.02-0.4 mm on a carrier is coated and the laminate obtained on the other side of the matrix with a Cover layer is provided. 8. The method according to claim 7, characterized in that one up to 150 ° C. heated polymer melt from (meth) acrylate copoly containing ammonio groups mers and citric acid triesters continuously oxybutynin as a solid substance is metered in so that a polymer melt with a content of up to 25 % By weight of oxybutynin and up to 33% by weight of citric acid triester is obtained and the active ingredient-containing polymer melt immediately after the addition of Active ingredient continuously in a thickness of 0.02-0.4 mm on a carrier is coated, the resulting 2-layer laminate is provided with a cover layer and then a larger patch free of active ingredient to fix the TTS on the Skin is applied.